Traditionally, neurological diseases have been classified into mechanistically distinct categories, such as neurodegenerative, inflammatory, and vascular. However, recent insights have led to a reassessment of the complex relationship between diseases and their mechanisms. Emerging evidence supports a role for vascular dysfunction as an early feature in AD that is an equal and independent predictor for cognitive decline compared to amyloid and correlates with worse prognosis in AD. However, the cellular and molecular mechanisms at the neurovascular interface that promote cognitive decline are poorly characterized. Furthermore, whether and how vascular alterations contribute to neuronal network and synaptic dysfunction, one of the earliest manifestations of AD, is unknown. A fundamental change at the neurovascular interface in AD is the deposition of the blood coagulation factor fibrinogen, which is deposited as insoluble fibrin in the AD brain. Our ultimate goal is to determine the dynamic interactions between innate immunity, vascular, and blood-derived signals and their causal relationships in regulating impaired synaptic activity as a prerequisite for devising novel therapies to improve synaptic and cognitive functions after vascular impairment. Studies from our laboratory and others have shown that genetic or pharmacologic depletion of the blood coagulation factor fibrinogen protects from neuroinflammation in several models of neurological disease. Our preliminary data demonstrate that dendritic spine elimination occurs around fibrinogen deposits in AD mice and fibrinogen-CD11b signaling promotes dendritic spine loss and cognitive impairment in AD mice. The four specific aims will are designed to determine the role of fibrinogen/CD11b signaling in microglial-synapse interactions and neuronal network abnormality, determine the mechanisms underlying fibrin-induced innate-immune driven neuronal dysfunction, and the therapeutic implications of targeting fibrin-microglia interactions in protecting from spine elimination and neuronal dysfunction. Our experimental design is based on a cutting-edge multi-pronged experimental approach consisting of in vivo two-photon imaging of neuronal activity and microglial dynamics, EM co-registration, iDISCO, unbiased transcriptomics and proteomics, and combined two-photon imaging with in vivo EEG recordings. The proposed studies will set the foundation how neurovascular dysfunction regulates synapse elimination and neuronal activity and the outcomes of this research would be applicable for the understanding of the etiology and the development of new treatments for vascular cognitive impairment including in AD and related conditions.